Comparative genomic analysis of proteome reduction in the apicomplexans

Abstract

Apicomplexans are alveolate parasites which include <em>Plasmodium falciparum</em>, the main cause of malaria, one of the world&rsquo;s biggest killers from infectious disease. Apicomplexans are characterized by a reduction in proteome size, which appears to result from metabolic and functional simplification, commensurate with their parasitic lifestyle. However, other factors may also help to explain gene loss such as population bottlenecks experienced during transmission, and the effect of reducing the overall genomic information content. The latter constitutes an &lsquo;informational constraint&rsquo;, which is proposed to exert a selective pressure to evolve and maintain genes involved in informational fidelity and error correction, proportional to the quantity of information in the genome (which approximates to proteome size).<br /> <br /> In this dissertation, the dynamics of gene loss is examined in 41 Apicomplexan genomes using orthogroup analysis. This work shows that loss of genes involved in amino acid metabolism and steroid biosynthesis can be explained by metabolic redundancy with the host. There is a marked tendency to lose DNA repair genes as proteome size is reduced. This may be explained by a reduction in size of the informational constraint and can help to explain elevated mutation rates in pathogens with reduced genome size.<br /> <br /> Effective population size (Ne) has a direct contribution to evolutionary changes. In these species, Ne is not well studied due to the morphological and genomic complexity. In order to measure Ne, model species <em>P. falciparum</em> is chosen whose mutation rate and generation time are already predicted. MSMC analysis indicates a recent bottleneck, consistent with predictions generated using allele-based population genetics approaches, implying that relaxed selection pressure due to reduced population size might have contributed to gene loss. However, the nonrandomness of pathways that are lost challenges this scenario.<br /> <br /> Malaria is an ancient disease and yet, there is no effective cure or prevention. This study looks for new antimalarial targets to identify unique orthogroups in malaria causing <em>Plasmodium</em> species that infect humans, with a high proportion of membrane associated proteins. Thus, orthogroup analysis appears useful for identifying novel candidate pathogenic factors in parasites, when there is a wide sample of genomes available.<br /> <br /> In terms of biodiversity, Apicomplexa has many unclear taxonomic structures. In this study, a statistically robust phylogeny is reconstructed by concatenating 522 genes from the core Apicomplexan genome which account for 6068 amino acid sequences. Different biases and pitfalls among alignments and phylogeny inference methods are also discussed.<br /> <br /> Lastly, this study provides a foundation for future experimental research, specific and comparative analysis of Apicomplexan proteomes.